The present invention, in some embodiments thereof, relates to combinations of anti ErbB antibodies for the treatment of cancer.
Pancreatic cancer is a malignant growth of the pancreas that mainly occurs in the cells of the pancreatic ducts. This disease is the ninth most common form of cancer, yet it is the fourth and fifth leading cause of cancer deaths in men and women, respectively. Cancer of the pancreas is almost always fatal, with a five-year survival rate that is less than 3%.
Current treatment procedures available for pancreatic cancer have not led to a cure, nor to a substantially improved survival time. Surgical resection has been the only modality that offers a chance at survival. However, due to a large tumor burden, only 10% to 25% of patients are candidates for “curative resection.” For those patients undergoing a surgical treatment, the five-year survival rate is still poor, averaging only about 10%.
Antibodies, in particular MAbs and engineered antibodies or antibody fragments, have been tested widely and shown to be of value in detection and treatment of various human disorders, including cancers, autoimmune diseases, infectious diseases, inflammatory diseases, and cardiovascular diseases. The clinical utility of an antibody or an antibody-derived agent is primarily dependent on its ability to bind to a specific targeted antigen associated with a particular disorder.
Tumor inhibition by mAbs is generally attributed to recruitment of effector arms by the antibodies as natural killer cells or by an antibody-dependent cell-mediated cytotoxicity (ADCC). Interaction of receptors with specific mAbs may obstruct cell function in other ways. MAbs can inhibit specific ligand binding, block heterodimerization or induce receptor internalization, thus directly decreasing the mitogenic signal. The evidence of inhibition of receptor phosphorylation or induction of receptor internalization in tumor cells argues in favor of other mechanisms induced directly by the mAb such as apoptotic or cytostatic signal transduced through the receptor. Thus, inhibition of tumor growth by mAbs can be attributed to a number of mechanisms investigated so far and probably to other yet unknown.
Interestingly, mAbs seem to display a synergistic effect when combined with chemotherapy, probably due to interruption of ErbB-2-driven survival pathways [Ben-Kasus T, Schechter B, Sela M, Yarden Y (2007) Cancer therapeutic antibodies come of age: Targeting minimal residual disease. Mol. Oncology 1: 42-54.]. Still another strategy, relevant to pancreatic cancer, combines antibodies to EGFR and to ErbB-2 [Larbouret C, Robert B, Navarro-Teulon I, Thezenas S, Ladjemi M Z, Morisseau S, Campigna E, Bibeau F, Mach J P, Pelegrin A, Azria D (2007) In vivo therapeutic synergism of anti-epidermal growth factor receptor and anti-HER2 monoclonal antibodies against pancreatic carcinomas. Clin Cancer Res 13: 3356-62; and WO 2007/076923].
Other art documents related to antibody combinations in the treatment of cancer include:
Drebin J. A. et al., Oncogene 2(3):273-277, 1988;
Kasprzyk et al., Cancer Res. 52(10):2771-2776, 1992;
Harwerth et al., Br. J. Cancer 68(6):1140-1145, 1993;
Spiridon et al. Clin. Cancer Res. 8:1720-1730, 2002;
Friedman et al. Proc. Natl. Acad. Sci. (2005) 102:1915-1920;
U.S. Pat. No. 7,498,142; and
WO2010/029534.